Transdermal system of tacrine/selegilin-plaster

ABSTRACT

The invention relates to a plaster for transdermal application with an outer covering or backing layer, a self-adhesive matrix or a reservoir and a removable protective liner or release layer, the matrix or the reservoir containing tacrine and selegiline (optionally in the form of their pharmaceutically compatible salts) as active substance.

This application is a 371 of PCT/EP96/04010, filed Sep. 12, 1996.

Tetrahydroaminoacridine (tacrine) is used as a centrally active cholineesterase inhibitor in the case of Alzheimer's disease. Its cholineesterase inhibition lasts for approximately 15 hours, i.e. considerablylonger than the half-life of tacrine which is in the region of 1.5 to3.5 h. The daily recommended dose varies between 30 and 160 mg, thetherapeutic blood level being in the range of 5 to 70 ng/ml and thebioavailability in the region of 10 to 30%. In the case of patients whosuffer from Alzheimer's disease and are being treated over a prolongedperiod with several doses of tacrine per day, a clinical improvement inthe memory and the functional autonomy can be observed.

Tacrine is used orally in the form of the hydrochloride (Cognex®). Sincethe oral administration of tacrine must take place in the form ofmultiple dosages, because of its short elimination half-life, while onthe other hand the release of the active substance should remainconstant over a long period, a transdermal administration wouldrepresent a more effective drug therapy. An additional problem is posedby the strong first pass metabolisation and the greatly varyingpharmacokinetics of tacrine which lead to a poor adjustability of thepatients, the occurrence of blood plasma peaks and an increase in thesecondary effects and the toxicity, particularly to the liver. Thehepatotoxic effect of tacrine occurs in the case of approximately halfof the patients, an increase in the ALT (alanine aminotransferase)values to as much as 20 times the upper normal limit being observed. Byway of a continuous transdermal administration of tacrine, more constantand lower therapeutically effective plasma levels and consequentlyreduced secondary effects, particularly on the liver, might be obtained,in particular since the high first pass effect and the lowbioavailability should no longer occur.

In EP-B-0 332 147, a transdermal system is described with a content of

(a) inter alia tetrahydroaminoacridine or a pharmaceutically acceptablesalt of this compound as active substance

(b) a propylene glycol diester of caprylic acid and capric acid(Migliol) and

(c) silicic acid as gelling agent.

Migliol increases the flow of substance through the skin of mice in thistransdermal system in comparison with a formulation without Migliol.Optionally, a permeation accelerator in the form of a solvent can beadded, e.g. alcohol. However, alcohol irritates the skin, dries it anddamages it. The use of ethanol should be assessed critically since itinterferes with the natural lipid layer of the skin and dries it andirritates it. In addition, it is stated in EP-B-O 499 662 that therelease control of the active substance in the case of plaster accordingto EP-B-O 332 147 is not an optimal one.

According to EP-B-O 499 662, a two-layer composite laminate is providedas transdermal system which consists of

A) a layer I with a component A which consists of solvent and an activesubstance in a partially cured elastomer and

B) a layer II on layer I which comprises a component B which consists ofa solvent and an active substance in a macroporous moulded body with apore size of 10 to 100 μm.

As an example of an active substance, 1,2,3,4-tetrahydro-9-acridinamine(THA=tacrine) is mentioned, inter alia. Alcohols, for example ethanol,are suggested as solvents for components A and B. However, ethanol againdries the skin, irritates and damages it.

Moreover, the spongy transdermal system known from EP-B-O- 499 662 isthick and inflexible and consequently not very practical for applicationby the patient since the system is exposed as a result of its height,easily involuntarily removable and does not adjust well to bodymovements.

The transdermal system known from EP-B-O 499 662 is produced by

(a) mixing an active substance with a solvent and a curable elastomercomponent

(b) the component A thus obtained is cast to form a partially curedlayer I

(c) an active substance is dissolved in a solvent

(d) the solution obtained is introduced into a macroporous moulded bodyand component B is obtained which forms layer II

(e) layer II is laminated onto layer I and, optionally, the laminatethus obtained is cut into plasters of the desired size.

This production process is difficult to understand, complicated and,moreover, leads to a poorly reproducible blood level, possibly as aresult of the partial curing of the elastomer which is difficult tocontrol. If, moreover, an elevated temperature of e.g. 160° C. is usedwith this highly costly process over several minutes, the activesubstance may be degraded as a result. Apart from the question of how analuminium foil should be laminated onto a macroporous sponge, thequestion remains unanswered as to how the transdermal system can beapplied onto the patient since obviously no adhesive element isprovided.

According to Auterhoff, Knabe & Holtge, Lehrbuch der PharmazeutischenChemie, edition 12, page 484, (R)(-)-N-methyl-N-(1-phenyl-2-propyl)-2-propinylamine(=selegiline=Deprenyl, commercially available as Movergan®), is ananti-Parkinson agent with a dopaminergic effect. EP-A-O 241 809describes a plaster (column 5, line 15) with a content of selegiline,this plaster being used in combination with a further plaster with acontent of amantadine. In addition, a plaster is known as TTS fromEP-B-O 404 807 with selegiline as the only active substance, the activesubstance penetrating from a matrix into the skin. DE-9 523 299describes a further transdermal system (TTS) with a covering film, alayer with a content of selegiline as active substance, a membrane, aself-adhesive layer and a removable protective layer.

Compared with this state of the art, it is a task of the invention toprovide a plaster for transdermal application with which Alzheimer'sdisease can be fought even more effectively. Another task of theinvention consist of increasing the skin permeation of the activesubstances and of tacrine in particular.

According to a first embodiment of the invention, a transdermal systemor plaster with an outer covering or backing layer, a self-adhesivematrix and a removable protective liner or release liner is provided forthis purpose, in the case of which the matrix contains

tacrine with selegiline (optionally in the form of theirpharmaceutically compatible salts) as active substance in addition to

a hydrophilic low volatility solvent and/or

a lipophilic low volatility solvent.

In view of the efforts made according to EP-B-O 499 662 to provide aplaster with a tacrine content, it could not be expected thatsatisfactory results could be achieved with a plaster according to theinvention. Moreover, the plaster according to the invention can bemanufactured cost effectively, reproducibly and without major thermalstress.

The plaster according to the invention is thin, can be tolerated by theskin, is flexible and can be highly satisfactorily applied onto theskin.

The plaster according to the invention differs from a plaster accordingto EP-B-O 332 147 in that the active substance or substances are notreleased from a gel using silicic acid as gelling agent but rather froma self-adhesive matrix containing no silicic acid. In the case of theplaster according to the invention it is also possible to deliberatelyabstain from providing the active substances in two different layersforming a laminate, as in the case of EP-B-O 499 662. Instead, theactive substances can be provided in a single layer of the plasteraccording to the invention, the layer being a self-adhesive matrix.

Since the recommended daily dose for the oral application of tacrine isin the region of 30 to 160 mg and the therapeutic blood level in theregion of 5 to 70 ng/ml, it could not be expected that a plaster fortransdermal application could be loaded with a comparable amount ofactive substance and that comparable blood levels could be achieved.

The plaster according to the invention may be characterised by a contentof up to 70% by weight (based on the weight of the matrix) of a solventfrom the group formed by hydrophilic low volatility solvents, lipophiliclow volatility solvents and their mixtures.

In the plaster according to the invention, the two active substances maybe present in the matrix in mixture. It is surprising in this respectthat the skin permeation can be increased by the presence of selegilinein comparison with a plaster with tacrine as the only active substance.

The matrix in the plaster according to the invention can also containtwo matrix layers in sequence, one matrix layer containing one and theother matrix layer the other of the two active substances, the matrixlayer adjacent to the outer covering or backing layer being able tocontain selegiline or one of its salts or tacrine or one of its salts asactive substance. In the case of this embodiment, the two matrix layersmay be separated by a membrane which controls the permeation of theactive substance from the matrix layer further removed from the skin.

In the plasters according to the invention, the matrix may also containtwo or more adjacent zones arranged side by side in the same plane, eachcontaining only one of the two active substances respectively. In thisembodiment, the zones may have the form of webs.

The content of tacrine and selegiline (optionally in the form of theirsalts) can be up to 50% by weight respectively (based on the weight ofthe matrix) in the plaster according to the invention.

The task on which the invention is based is achieved according to afurther embodiment by a plaster for transdermal application with anouter covering or backing layer, a reservoir, an adhesive element forcontact between the plaster and the skin and a removable protectiveliner or release liner, the reservoir containing

tacrine and selegiline (optionally in the form of their pharmaceuticallycompatible salts) as active substances in addition to

a solvent from the group formed by hydrophilic low volatility solvents,hydrophobic low volatility solvents, monohydric C₂₋₄ alcohols, ethyleneglycol and their mixtures.

According to the invention, a membrane, in particular a membranecontrolling the permeation of active substance, can be provided.

Membrane and reservoir plasters are part of the state of the art. As anexample only, reference should be made to WO-A1-89/09 051, WO-A1-94/23707, EP-B1-O 404 807 and EP-A1-O 406 488.

For the plaster according to the invention, it is possible to provide amatrix based on polyacrylate, silicone or polyisobutylene. Such matricesare anticipated in the state of the art. As an example only, referenceshould be made to DE-B-3 933 460 for a polyacrylate matrix, to DE-A-4339 400 for a silicone matrix and to EP-A-0 186 019 for apolyisobutylene matrix.

In the case of the said embodiment of the plaster according to theinvention, the reservoir can be formed by the outer covering or backinglayer and the membrane or by a matrix.

The adhesive element can be provided in the form of a layer covering thereservoir (if there is no membrane) or the membrane completely or onlyon its periphery in an annular manner. According to the invention, theadhesive element can consist of a pressure-sensitive adhesive based onsilicone.

The plaster according to the invention can also be characterised by acontent of α-tocopherol or α-tocopherol derivative. By means of thisaddition it is possible to take the critical skin compatibility in thecase of the application of low alcohols into account.

It is possible to use, for example, propylene glycol, 1,2-pentane diol,glycerine, hydrophilic Cetiol or Transcutol® as hydrophilic lowvolatility solvent for a plaster according to the invention. Propyleneglycol and glycerine have already been suggested in EP-B-0 499 662,though for the deviating transdermal system discussed above.

Moreover, Copherol®, propylene glycol dicaprylate/dicaprate such asMigliol®, isopropyl myristate or lipophilic Cetiol®, e.g. Cetiol HE, forexample, can be used as lipophilic low volatility solvent for theplaster according to the invention. Isopropyl myristate has already beensuggested in EP-B-0 332 147 and Migliol® in EP-B-0 332 147 and EP-B-0499 662, though for the deviating transdermal systems discussed above.

In the case of the plaster according to the invention it is particularlysurprising that a combination of hydrophilic low volatility solventswith lipophilic low volatility solvents leads to a substantially higherrate of skin permeation than with each solvent alone.

The plaster according to the invention may also contain aviscosity-enhancing agent such highly dispersed silicon dioxide orhydroxypropylcellulose.

Below, the invention will be explained in further details by examples.

EXAMPLE 1 Single Layer TTS with Tacrine/Selegiline

tacrine and selegiline base are dissolved in ethanol. The solutionobtained is added to a solution of acrylate adhesive (e.g. Duro-Tak®such as Duro-Tak® 326-1753; National Starch & Chemicals) in ethylacetate and n-hexane and, optionally, it can be mixed with furtherauxiliary agents. Subsequently, the solution is applied by means of adoctor blade onto a siliconised polyester film as peel-off film (e.g.Hostaphan®, Hoechst) with a wet layer thickness of 450 μm and dried for1 hour at 50° C. The dried layer is laminated with a polyester film (orany other suitable covering film). Using a punch, TTS with a surfacearea of 10, 20, 30 and 40 cm² are punched from the laminate.

EXAMPLE 2 Two-Layer TTS without a Membrane Controlling the Release ofActive Substance

Layer A; tacrine base is dissolved in ethanol (optionally together withauxiliary agents). The solution obtained is added to a solution ofacrylate adhesive (e.g. Duro-Tak®, such as Duro-Tak® 326-1753; NationalStarch & Chemicals) in ethyl acetate and n-hexane and mixedhomogeneously (optionally with other auxiliary agents). The solution isapplied by means of a doctor blade onto a siliconised polyester film(e.g. Gelroflex®, Rexam Release) as peel off film with a wet layerthickness of 450 μm and dried for 1 hour at 50° C.

Layer B; this layer is prepared in an analogous manner to layer A with asingle exception, namely that the tacrine base is replaced by theselegiline base.

Subsequently, the dried layer A is laminated onto the second layer B.The peel-off film of the selegiline layer B is peeled off from thetwo-layer TTS obtained in this way, subsequent to which a thin polyesterfilm (e.g. Hostaphan®; Hoechst) is applied as outer covering layer(backing film) as a replacement for the peeled off film.

EXAMPLE 3 Two-Layer TTS with a Membrane Controlling the Release ofActive Substance

In the same way as in example 2, two layers A and B are prepared;however, a membrane controlling the permeation of active substance isprovided between these two layers (e.g. Cotran® from 3M; or 1154P). Thistwo-layer TTS is again formed in such a way that it can be bonded ontothe skin with the layer containing tacrine.

EXAMPLE 4 Dual Web TTS

Tacrine base on the one hand and selegiline base on the other hand aredissolved according to example 2 and mixed with the acrylate adhesive.Subsequently, two separate webs are laminated side by side onto a peeloff film in such a way that one layer contains tacrine and the otherlayer selegiline. After drying of the dual web layer and laminating anouter covering or backing layer on to it, TTS are punched which containone web of tacrine and selegiline respectively. Obviously, theproportions of the two active substances can be variably adjusted.

EXAMPLE 5

A pressure-sensitive adhesive based on silicone (trimethylated silicondioxide treated with polydimethyl siloxane with terminal trimethylsiloxy groups; layer thickness in the dry state (LT) approximately 35 to45 μm; substance weight (SW) approximately 50 to 60 g/m²) was used forthe i- adhesive layer. An outer covering or backing layer of PET(thickness approximately 75 μm, SW approximately 100 g/m²) was coatedwith the silicone adhesive using a coating device. On to the coatedouter covering or backing layer, a microporous polypropylene membrane(heat sealable; thickness approximately 50 μm, SW approximately 120g/m²) was laminated in such a way that a laminate consisting of thecovering layer, adhesive and membrane was produced. Subsequently, thelaminate was welded by means of a sealing machine (with welding ring) toa carrier film of polyester (aluminium-metalised) with a polyolefinsealant layer (heat sealable; thickness approximately 70 μm) in such away that a gap remained for introducing a solution of active substance.The fillable transdermal therapeutic system (empty TTS) was filled e.g.with a Hamilton syringe or with a hose pump with a hollow needle withthe following solution of active substance:

Composition of the solution of active substance per TTS:

    ______________________________________                                                            mg/TTS                                                    ______________________________________                                        Tacrine base           40.0                                                     Selegiline base                   20.0                                        Propylene glycol                    160.0                                     α-Tocopherol                   80.0                                     Total                               300.0 mg                                ______________________________________                                    

Quantity introduced into the reservoir: 300.0 mg

After filling, the gap used for filling was sealed. Filled transdermaltherapeutic systems were punched out by means of a punch.

We claim:
 1. A plaster for transdermal application said plastercomprising an outer backing layer, a self-adhesive matrix, and aremovable release layer, said matrix further comprising:A) a firstactive substance comprising tacrine or a pharmaceutically compatiblesalt thereof, and a second active substance comprising selegiline or apharmaceutically compatible salt thereof; and B) a low volatilitysolvent selected from the group consisting of hydrophilic solvents,lipophilic solvents, and mixtures thereof.
 2. A plaster according toclaim 1 wherein said low volatility solvent comprises up to 70 percentby weight of said matrix.
 3. A plaster according to claim 1 wherein bothof said active substances are present in the matrix in admixture.
 4. Aplaster according to claim 1 wherein said matrix contains two matrixlayers in sequence, one matrix layer containing said first activesubstance, and a second matrix layer containing said second activesubstance.
 5. A plaster according to claim 4 wherein a matrix layeradjacent to the outer backing layer contains said first active substanceor said second active substance.
 6. A plaster according to claim 4wherein said two matrix layers are separated by a membrane controllingactive substance permeation.
 7. A plaster according to claim 1 whereinsaid matrix comprises two or more adjacent zones arranged side by sidein the same plane, each of said zones containing only one of said firstand second active substances.
 8. A plaster according to claim 7 wheresaid zones are in the form of webs.
 9. A plaster according to claim 1wherein said first active substance and said second active substancetogether comprise up to 50 percent by weight based on the weight of thematrix.
 10. A plaster for transdermal application of tacrine andselegiline comprising an outer covering or backing layer, a reservoir,an adhesive element for contact between said plaster and the skin of apatient, and a removable protective liner or release liner, saidreservoir comprising:A) a first active substance comprising tacrine or apharmaceutically compatible salt thereof and a second active substancecomprising selegiline or a pharmaceutically compatible salt thereof; andB) a low volatility solvent selected from hydrophilic solvents,hydrophobic solvents, and mixtures thereof, and C) optionally,monohydric C₂₋₄ alcohols, ethylene glycol, and mixtures thereof.
 11. Aplaster according to claim 10 further comprising a membrane whichcontrols active substance permeation into the skin.
 12. A plasteraccording to claim 11 wherein said reservoir is formed by said outercovering or backing layer and said membrane.
 13. A plaster according toclaim 10 wherein said matrix comprises a polyacrylate polymer, asilicone polymer, or a polyisobutylene polymer.
 14. A plaster accordingto claim 1 wherein said matrix comprises a polyacrylate polymer, asilicone polymer, or a polyisobutylene polymer.
 15. A plaster accordingto claim 10 further comprising an adhesive element in the form of alayer completely covering said reservoir.
 16. A plaster according toclaim 10 further comprising an adhesive element covering the peripheryof said membrane in an annular manner.
 17. A plaster according to claim10 further comprising an adhesive element comprising a pressuresensitive silicone adhesive.
 18. A plaster according to claim 1 furthercomprising α-tocopherol or derivative thereof.
 19. A plaster accordingto claim 10 further comprising α-tocopherol or derivative thereof.
 20. Aplaster according to claim 1 wherein said hydrophilic low volatilitysolvent comprises propylene glycol, 1,2-pentane diol, glycerin,2-(2-ethoxyethoxy)ethanol, and mixtures thereof.
 21. A plaster accordingto claim 10 wherein said hydrophilic low volatility solvent comprisespropylene glycol, 1,2-pentane diol, glycerin, 2-(2-ethoxyethoxy)ethanol,and mixtures thereof.
 22. A plaster according to claim 1 wherein saidlipophilic low volatility solvent is selected from the group consistingof propylene glycol dicaprylate/dicaprate, i-propyl myristate, andmixtures thereof.
 23. A plaster according to claim 10 wherein saidlipophilic low volatility solvent is selected from the group consistingof propylene glycol dicaprylate/dicaprate, i-propyl myristate, andmixtures thereof.
 24. The plaster of claim 1, wherein said lowvolatility hydrophilic solvent is selected from the group consisting ofpropylene glycol, 1,2-pentane diol, glycerine,2-(2-ethoxyethoxy)ethanol, and mixtures thereof, and wherein saidliophilic low volatility solvent is selected from the group consistingof propylene glycol dicaprylate/dicaprate, i-propyl myristate, andmixtures thereof.
 25. The plaster of claim 10, wherein said lowvolatility hydrophilic solvent is selected from the group consisting ofpropylene glycol, 1,2-pentane diol, glycerine,2-(2-ethoxyethoxyl)ethanol and mixtures thereof, and wherein saidliophilic low volatility solvent is selected from the group consistingof propylene glycol dicaprylate/dicaprate, i-propyl myristate, andmixtures thereof.